Tight junction dysfunction in the stratum granulosum leads to aberrant stratum corneum barrier function in claudin-1-deficient mice

Sugawara, Tomoko; Iwamoto, Noriko; Akashi, Mitsuru; Kojima, Takanori; Hisatsune, Junzo; Sugai, Motoyuki; Furuse, Mikio

doi:10.1016/j.jdermsci.2013.01.002

Cited by 120 publications

(121 citation statements)

References 54 publications

(71 reference statements)

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“…These results are consistent with a scenario in which aberrant MYD88-dependent activation of RABdin 1 (4,5,19,55,56). The changes observed in filaggrin expression may in part reflect the decreased expression of claudin 1, as claudin 1-deficient keratinocytes display defects in filaggrin processing (57). However, keratinocytes from filaggrin-deficient mice, unlike keratinocytes in mice selectively deficient in keratinocyte RABGEF1, display intact TJs (58).…”

Section: Discussionsupporting

confidence: 85%

Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis

Marichal¹,

Gaudenzio²,

Abbas³

et al. 2016

Journal of Clinical Investigation

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, 2-way ANOVA with Bonferroni's test for multiple comparisons (G and K), or Mann-Whitney test (L). *P < 0.05; **P < 0.01; ***P < 0.001. Scale bars: 50 μm; original magnification in B and I, ×20; NS, not significant. The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 4 9 9 jci.org Volume 126 Number 12 December 2016 some expression of keratin 14 (K14) in epithelial cells. However, these organs did not exhibit histological abnormalities (Supplemental Figure 3). These results indicate that the cause of death in such mice is more likely related to the skin abnormalities. Because of the accelerated mortality in Rabgef1 K-KO mice, and to assess the function of keratinocyte-intrinsic RABGEF1 in adult mice that would exhibit no potential developmental effects of constitutive Rabgef1 deletion, we generated mice in which Rabgef1 can be depleted in keratinocytes by tamoxifen treatment, i.e., K14-Cre-ERT2 + Rabgef1 fl/fl mice (called Rabgef1 KERT2-KO mice). Topical tamoxifen treatment on the back skin of adult Rabgef1 KERT2-KO mice, but not adult Rabgef1 fl/fl mice, promoted the development of skin lesions that were similar to those in Rabgef1 K-KO mice and were associated with RABGEF1 deletion in keratinocytes (Figure 1, H-K). Such skin lesions were associated with a modest, albeit statistically significant, increase in the number of bacteria that could be cultured from the affected skin ( Figure 1L), but not with evidence of associated systemic bacterial infection (Supplemental Figure 4).RABGEF1 deletion in keratinocytes results in epidermal barrier dysfunction, features of type 2 skin inflammation, and elevated levels of IgE antibodies. Histological and immunohistological analyses of back skin from newborn mice did not reveal obvious differences between Rabgef1 K-KO and control mice (Supplemental Figure 5). By contrast, back skin lesions of postnatal day 7-9 as well as day 49-56 (i.e., adult) Rabgef1 K-KO mice exhibited marked epidermal hyperplasia (Figure 1, F and G) and spongiosis ( Figure 2A These observations prompted us to investigate whether keratinocyte-intrinsic RABGEF1 deficiency resulted in epidermal barrier dysfunction. We used our model of inducible keratinocyte Rabgef1 deletion by topical tamoxifen treatment of Rabgef1 KERT2-KO mice and assessed barrier function by measuring transepidermal water loss (TEWL) (ref. 36 and Figure 2F). As shown in Figure 2G, TEWL was significantly increased in the back skin of tamoxifen-treated Rab gef1 KERT2-KO mice versus tamoxifen-treated control mice. Consistent with the increased permeability of the skin, the transepidermal passage of a harmless antigen, ovalbumin (OVA), patched on the skin was also potentiated when RABGEF1 was defective in keratinocytes. Indeed, dermal DC uptake and endosomal digestion of OVA was also substantially induced in tamoxifen-treated Rabgef1 KERT2-KO mice, whereas OVA was less accessible to DCs in vehicle-treated Rab gef1 KERT2-KO mice or tamoxifen-treated littermate control mice ( Figure 2H).(DCs) with the capacity to induce a ...

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Section: Discussionsupporting

confidence: 85%

Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis

Marichal¹,

Gaudenzio²,

Abbas³

et al. 2016

Journal of Clinical Investigation

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“…Under homeostatic conditions a proper differentiation process is required to form competent TJ structures; consequently, abnormal TJ formation should be expected in the context of processes that impair differentiation. On the other hand, abnormal epidermal TJ could lead to impaired terminal differentiation process, as has been shown in the cldn-1 knockout mice (e.g., abnormal lipids profile, defective processing of profilaggrin to filaggrin) 32 and reconstructed human skin with occludin knockdown 20 (see also 18 for the correlation of differentiation and TJs).…”

Section: Tj and Adaptive Immune Barriermentioning

confidence: 95%

“…First, the abnormal water loss observed in the homozygous mice may be a downstream effect of Cldn-1 KO on SC proteins and lipids which leads to the impaired water barrier. 24,31,32 Indeed, Sugawara et al 32 recently demonstrated that Cldn-1 KO mice have an abnormal SC based on alterations in ceramide composition and filaggrin processing as well as enhanced water evaporation. Second, we can speculate that residual amount of cldn-1 (at least in the human siRNA knock-down experiments and in the Cldn-1 heterozygous mice) may be sufficient to control water flux.…”

Section: Tj Composition and Function In Healthy Skin (And Cultured Kementioning

confidence: 99%

Epidermal tight junctions in health and disease

et al. 2014

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“…In the skin, TJs are key contributors to the epidermal paracellular barrier, and claudin-1 (CLDN1), a main component of TJs in the epidermis, is reported to be indispensable for this barrier function; abnormalities in CLDN1 cause human skin diseases (5)(6)(7)(8)(9). However, because Cldn1 knock-out (KO) mice die within 1 d of birth due to dehydration (10,11), it has been difficult to study how Cldn1 contributes to skin diseases.…”

mentioning

confidence: 99%

Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis

Tokumasu

Yamaga

Yamazaki

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

116

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Atopic dermatitis (AD) is a chronic inflammatory skin disease in humans. It was recently noted that the characteristics of epidermal barrier functions critically influence the pathological features of AD. Evidence suggests that claudin-1 (CLDN1), a major component of tight junctions (TJs) in the epidermis, plays a key role in human AD, but the mechanism underlying this role is poorly understood. One of the main challenges in studying CLDN1's effects is that Cldn1 knock-out mice cannot survive beyond 1 d after birth, due to lethal dehydration. Here, we established a series of mouse lines that express Cldn1 at various levels and used these mice to study Cldn1's effects in vivo. Notably, we discovered a dose-dependent effect of Cldn1's expression in orchestrating features of AD. In our experimental model, epithelial barrier functions and morphological changes in the skin varied exponentially with the decrease in Cldn1 expression level. At low Cldn1 expression levels, mice exhibited morphological features of AD and an innate immune response that included neutrophil and macrophage recruitment to the skin. These phenotypes were especially apparent in the infant stages and lessened as the mice became adults, depending on the expression level of Cldn1. Still, these adult mice with improved phenotypes showed an enhanced hapten-induced contact hypersensitivity response compared with WT mice. Furthermore, we revealed a relationship between macrophage recruitment and CLDN1 levels in human AD patients. Our findings collectively suggest that CLDN1 regulates the pathogenesis, severity, and natural course of human AD.claudin-1 | tight junctions | atopic dermatitis

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Tight junction dysfunction in the stratum granulosum leads to aberrant stratum corneum barrier function in claudin-1-deficient mice

Cited by 120 publications

References 54 publications

Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis

Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis

Epidermal tight junctions in health and disease

Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis

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